9-cis Retinoic acid and 1.25-dihydroxyvitamin D3 drive differentiation into IgA+ secreting plasmablasts in human naïve B cells.

Calcitriol and 9-cis retinoic acid (9cRA) play a fundamental role in shaping the adaptive immune response by altering the Ig profile and the differentiation of B cells, controlled by their corresponding nuclear receptors, VDR and RAR. Herein, after the establishment of a plasmablast differentiation culture, we investigated how both ligands modulate human naïve B cell differentiation and to which extent VDR/RXR and RAR/RXR signaling interferes. Calcitriol and 9cRA mediated activation of purified naïve B cells resulted in a strong differentiation of CD27+ CD38+ plasmablasts and antibody secretion. The significant IgA response was preceded by a strong induction of α-germline transcription (GLT). Induction of αGLT and consecutively IgA secretion driven by calcitriol is a novel observation and we show by magnetic chromatin IP that this was mediated by recruitment of the VDR to the TGF-ß promoter thus inducing TGF-ß expression. Finally, as revealed by transcriptomic profiling calcitriol and 9cRA modulate several signals required for differentiation and isotype switching in a noncompeting but rather additive manner. Calcitriol and 9cRA participate in the control of the IgA response in human activated naïve B cells. The balance between both ligands may be an important factor in channeling humoral immune responses toward a protective direction.

9-cis retinoic acid modulates the type I allergic immune response.

BACKGROUND: Vitamin A is a potent regulator of adaptive immunity. The effect of the endogenous metabolite 9-cis retinoic acid (9cRA) on allergic sensitization is unknown. OBJECTIVE: We sought to investigate whether and to what extent 9cRA modulates the humoral immune response. METHODS: BALB/c mice were sensitized and challenged with ovalbumin (OVA). 9cRA was applied repeatedly together with the antigen. Immunoglobulin production and cellular analysis were performed by using ELISA, ELISpot, and flow cytometry. Human CD19+ B cells were activated in vitro in the presence or absence of 9cRA and activation markers, and proliferation and secreted immunoglobulin levels were analyzed by using flow cytometry and ELISA. RESULTS: 9cRA applied together with repeated OVA challenge transiently increased specific serum IgA, IgE, and IgG1 serum levels (2.0- and 8.9-fold). After OVA recall, specific IgE concentrations were reduced by a mean of 57% after adding 9cRA, whereas IgA was strongly induced (20-fold), and IgG1 levels remained unchanged. Correspondingly, less specific IgE- and more IgA-secreting cells resided in the spleen in the 9cRA groups. Additionally, 9cRA promoted the migration of specific B cells to the mesenteric but not draining lymph nodes. In purified stimulated human B cells, 9cRA markedly reduced IgE production and enhanced IgA production. B-cell activation was modulated by 9cRA, reducing the expression of CD86 and promoting IL-10. CONCLUSIONS: Our data indicate that 9cRA modulates the allergic immune response by reducing the IgE response but promoting the IgA response. Thus 9cRA can modulate the allergic immune response toward a non-IgE condition.

Endogenous Calcitriol Synthesis Controls the Humoral IgE Response in Mice.

The vitamin D receptor participates in the control of IgE class-switch recombination in B cells. The physiologic vitamin D receptor agonist, 1,25(OH)2D3 (calcitriol), is synthesized by the essential enzyme 25-hydroxyvitamin D3-1α-hydroxylase (CYP27B1), which can be expressed by activated immune cells. The role of endogenous calcitriol synthesis for the regulation of IgE has not been proven. In this study, we investigated IgE-responses in Cyp27b1-knockout (KO) mice following sensitization to OVA or intestinal infection with Heligmosomoides polygyrus Specific Igs and plasmablasts were determined by ELISA and ELISpot, Cyp27b1 expression was measured by quantitative PCR. The data show elevated specific IgE and IgG1 concentrations in the blood of OVA-sensitized Cyp27b1-KO mice compared with wild-type littermates (+898 and +219%). Accordingly, more OVA-specific IgG1-secreting cells are present in spleen and fewer in the bone marrow of Cyp27b1-KO mice. Ag-specific mechanisms are suggested as the leucopoiesis is in general unchanged and activated murine B and T lymphocytes express Cyp27b1 Accordingly, elevated specific IgE concentrations in the blood of sensitized T cell-specific Cyp27b1-KO mice support a lymphocyte-driven mechanism. In an independent IgE-inducing model, i.e., intestinal infection with H. polygyrus, we validated the increase of total and specific IgE concentrations of Cyp27b1-KO compared with wild-type mice, but not those of IgG1 or IgA. We conclude that endogenous calcitriol has an impact on the regulation of IgE in vivo. Our data provide genetic evidence supporting previous preclinical and clinical findings and suggest that vitamin D deficiency not only promotes bone diseases but also type I sensitization.